At present, there are no effective oral delivery systems that will release drugs continuously at therapeutic levels for extended periods to treat bacterial, fungal or viral infections in immunocompromised patients. We expect that direct local delivery of drugs to the infected sites will be efficacious and will omit the need for systemic treatment of these conditions, thereby avoiding side effects that are observed with systemic administration. This proposed project is to develop improved biocompatible polymeric devices. These devices should provide a continuous intraoral release of therapeutic agents including antimicrobial, antifungal and antiviral drugs currently being used in the treatment of patients suffering from oral conditions such as Candida albicans and viral infections in AIDS patients. The proposed studies are focused on optimizing the drug delivery characteristics of an FDA approved polymeric material, ethylene vinyl acetate (EVA) copolymer as a mouth guard device for sustained release of current FDA approved therapeutic agents, chlorhexidine, nystatin, ganciclovir and acyclovir, alone or in combination. The efficacies of the released drugs will be measured as released from the EVA or other biocompatible polymer based devices. Based on the results of in vitro studies, clinical trials will be performed with customized drug-impregnated mouth guards testing safely and efficacy. The hypothesis to be testedis that the intra-oral continuous release of antimicrobial agents from polymeric devices at therapeutic levels will be effective in decreasing the oral burden of pathogens causing oral infections. Based on the results of in vitro studies, an ascending dose trial will be performed to determine safety, drug delivery, and bioavaUability. Clinical efficacy of the therapeutic agents to treat periodontal diseases and herpetic lesions in patients with oral disease will be evaluated against controls. Improvements of periodontal disease status and herpetic lesions in patients with oral disease will be evaluated against controls. Effects of drugs on levels of bacterial pathogens in plaque and saliva samples from drug-treated AIDS patients will be assessed in our oral microbiology diagnostic facility (CLIA-certified) and in a laboratory of oral virology. These proposed studies will establish the basis for a new and novel procedure for sustained local drug delivery over extended time periods using laboratory methods and materials that are readily available to dentists. The effective and efficient controlled drug release devices could have broad therapeutic applications in immunocompromised patients.